Regulation of BRCA1-BARD1 heterodimers by post-translational modifications. Relevance in cancer.
Post-translational modifications (PTMs) are chemical modifications that play a key role in protein regulation, as they can regulate activity, localization and interaction with other proteins, or DNA. The relevance of PTMs in cancer development is well established.
BRCA1 is a protein with a role in regulating DNA repair, chromatin remodelling, cell cycle progression, transcription, cell survival/apoptosis and regulation of centrosome duplication. In healthy cells BRCA1 maintain proper genomic repair and cell division, but inherited mutations in the BRCA1 predispose women to development of breast and ovarian cancer. In addition, impairment of BRCA1 pathways, by deregulation or reduced expression of BRCA1 is likely responsible for basal-like breast cancer, a subset of breast cancer associated with poor prognosis and resistance to treatment, implying the importance of BRCA1 not only in familial breast cancers but also in sporadic cancers. It is well established its regulation at transcriptional level, however, its regulation at post-translational level remains poorly understood.
In vivo, most of BRCA1 exists as a heterodimer with the BARD1 and many of its biological functions are mediated by the BRCA1-BARD1 complex.
BARD1 is an important regulator of the tumour-suppressor function of BRCA1, as well as acting as a tumour suppressor itself. BARD1 is indispensable for cell viability, so loss-of-function mutations are rare, but mutations and posttranslational modifications that alter its function might be involved in the pathogenesis of breast cancer.
With this project we plan to study post-translational modifications of the BRCA1-BARD1 heterodimer, their upstream regulation and downstream consequences, and the relevance of those modifications in breast and ovarian cancer.
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FTE Category A staff submitted: 49.50
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